Idiopathic pulmonary fibrosis (IPF) is a dreaded fibrotic lung disease that is refractory to usual medical treatments and has a dismal prognosis. Recent findings of our research group, as well as others, include evidence of adaptive immunologic processes in IPF patients that fulfill conventional criteria of autoimmunity. Among other observations, a cohort of IPF patients have autoantibodies against heat shock protein 70, along with evidence of pathogenecity, and the presence of this autoimmune response is associated with worse subsequent outcomes of the afflicted patients. Autoimmune responses tend to be self-perpetuating, and often respond poorly to nonspecific immunosuppressant treatments. The presence of pathogenic autoimmune responses could contribute to the unremitting nature and refractoriness of IPF to previous treatments. These and other, related findings lead us to posit the central hypothesis of this application: Antibody-mediated autoimmunity can play an important role in IPF progression. The research proposed here will elucidate pathogenic mechanisms of IPF autoantibodies by in vitro assays that measure effects of patient-derived IgG on primary human lung cells (Specific Aim 1), discover other clinically-important IPF autoantibodies by use of high-throughput antigen arrays (Specific Aim 2), and provide materials for later detailed investigations by cloning IgG genes of IPF patients (Specific Aim 3). The findings of these studies will result in greater understanding and appreciation of autoimmune processes that contribute to IPF progression, thereby challenging current paradigms of disease pathogenesis, and identify immunologic bioassays that could be useful for prognostications of individual IPF patients. Most importantly, the findings here will result in further interest and justification for a clinical trial of mechanistically-focused, and potentially more efficacious, immune modulation of IPF patients (e.g., specific anti-B-cell agents), to follow in subsequent incremental continuation proposals. RELEVANCE (See instructions): Idiopathic pulmonary fibrosis (IPF) is a dreaded, and usually fatal lung disease of older adults. No medical treatments are known to be effective for IPF. We have found evidence that autoimmunity appears to be involved in IPF, in which the patient's own immune system attacks the lung. These findings raise the possibility that treatments that target these autoimmune process may be more effective for IPF. Also, there was a sense that the autoantibody data provided may be easily misinterpreted and that much work must precede a therapy based on this approach.